Using the piglet as a model for the human infant, the goal of this study was to compare dietary lipid matrices found in infant formula and maternal milk on post-natal neurodevelopmental patterns. Over a 25-day feeding study, piglets (n=9-10 per treatment, 1.5 ± 0.2 kg initial BW) were either sow-reared (SR) with ad libitum intake, or artificially-reared (AR) receiving 1 of 3 milk replacers modified to mimic the nutritional profile and intake pattern of sow’s milk. Our AR treatments included: T1, artificially-reared (AR) control formula; T2, T1 + 45% total dietary fat replaced with pre-digested fat (PDF); T3, T2 + 10% lecithin + 0.4% cholesterol. Sow-reared animals were used as a positive control for study outcomes. Piglets were weighed daily, serum samples were collected at d 0, d 14, and d 25 of study, and fecal samples were collected, and pooled from d 13-27. At 3 weeks of age, piglets were subjected to a standardized set of magnetic resonance imaging (MRI) procedures to identify macro- and micro-structural characteristics of the brain. At study conclusion, piglets were euthanized and tissues were collected for further analysis. For the duration of the study, SR piglets exhibited higher BW gain and heavier extracted whole brain weights compared with AR piglets. Analysis of fecal fat suggested greater (P < 0.05) excretion of dietary fat with addition of PDF along with lecithin and cholesterol. Serum lipid profiling at d 14 and d 25 of study revealed serum triglycerides (TAG) concentrations to be higher (P = 0.176, P = 0.164) in T3-fed piglets when compared with T1- and T2-fed piglets. Furthermore, serum cholesterol concentrations were higher (P < 0.05) in T3-fed piglets when compared with T1- and T2-fed piglets on d 25 of study. Furthermore, hippocampal tissue analysis revealed neutral lipid (NL) docosahexaenoic acid (DHA) concentrations were greater (P < 0.05) in T3-fed pigs compared with T1-fed and SR pigs. Hippocampal phospholipid (PL) DHA concentrations of T2- or T3-fed pigs were intermediate to T1-fed and SR piglets. Diffusion tensor imaging, a MRI sequence that characterizes brain microstructure, revealed that SR piglets had greater (P < 0.05) average whole-brain fractional anisotropy (FA) values compared with AR piglets, suggesting differences in white matter organization. Although global analysis did not reveal differences within AR treatments for DTI outcomes, FA values of the internal capsule were not different between SR and T3-fed piglets, suggesting a modulatory effect of PDF + lecithin + cholesterol fat system on white matter maturation. Higher fecal fat excretion, partnered with higher serum TAG concentrations in T3-fed piglets as compared with other AR treatments, suggested higher bioavailability of the PDF when supplemented with lecithin and cholesterol. Elevated serum cholesterol at d 25 of study, partnered with elevated hippocampal DHA concentrations of T3-fed animals suggested higher bioavailability of the PDF, especially when supplemented with lecithin and cholesterol. Higher FA values in the internal capsule of T3-fed piglets indicate higher myelination of this early maturing white matter rich region as compared with other AR treatments, and may be impacted by elevated serum cholesterol concentrations. As the animal matures in age, the 2-fold elevation of hippocampal DHA seen in T3-fed piglets, as compared with control or SR animals, may produce similar elevations white matter maturation in the hippocampus as seen in the IC. Overall, our results indicate differential patterns of white matter development between AR and SR animals, and replacing part of formula TAG with PDF, and addition of lecithin and cholesterol, may elicit preferential accretion of brain DHA due to compositional manipulations of the dietary lipid matrix.